There are a large number of anticancer agents such as anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer agents, anticancer platinum coordination compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers and other anticancer agents, and one of the preferred cancer therapies has been combination chemotherapy with those anticancer agents. Their anticancer effects are, however, insufficient. One of these explanations is many types of cancers have activated PI3K pathway which prohibits tumor cells from cell death and weaken the anti-tumor efficacy by these agents. Most of these agents do not target PI3K pathway, thus did not solve the chemoresistance due to activation of this pathway. Moreover, most of these agents are not selective to tumor cells, thus side-effect was often enhanced by co-administration of cytotoxic agents. Thus, a provision of novel cancer therapy is strongly desired.
The Ser/Thr kinase Akt lies at a critical signaling node downstream of PI3K and plays an important role in promoting cell survival and inhibiting apoptosis. Direct therapeutic intervention with an Akt inhibitor may be advantageous in cancers where increased Akt signaling is associated with reduced sensitivity to cytotoxic agents or some receptor tyrosine kinase inhibitors. However, specific combination of an Akt inhibitor with other anticancer agents useful in the field of cancer therapy has not been reported.
On the other hand, WO2008/070016 and WO2008/070041 disclose 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3(2H)-one or a pharmaceutically acceptable salt thereof, and various Akt inhibitors as well as other anticancer agents. However, these references do not describe the specific combination cancer therapy with the Akt inhibitor and other anticancer agents.